1. Field of the Invention
This invention relates to novel furan nitrone compounds and their use as free radical trapping agents and therapeutic agents. More particularly, this invention concerns furan nitrone compounds and their use as analytical reagents for detecting free radicals and as therapeutics for treating various medical dysfunctions and diseases.
2. State of the Art
Nitrones, such as xcex1-phenyl-N-ter-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), are known to be useful as analytical reagents for detecting free radicals. Such compounds function as xe2x80x9cspin trapsxe2x80x9d by reacting with unstable free radicals to form relatively stable free radical spin adducts which are observable by electron spin resonance (ESR) spectroscopy. Thus, spin trapping allows previously unobservable free radicals to be identified and studied using ESR and related techniques.
The use of nitrones as spin traps for studying unstable free radicals has been applied to biological systems. In this regard, PBN, DMPO and related compounds have been used to identify superoxide (O2xe2x88x92.) and hydroxyl radicals (HO.) in biological systems. Additionally, such nitrones have been used to study lipid peroxidation and other free radical-induced biological processes.
More recently, nitrone compounds, such as PBN and derivatives thereof, have been reported as therapeutics for the treatment of a wide variety of disease conditions arising from or characterized by free radical-induced oxidative damage. Such disease conditions include, for example, disorders of the central nervous system (CNS) and the peripheral nervous system, such as stroke, Parkinsonism, traumatic nerve damage and the like, and disorders of the peripheral organs, such as atherosclerosis, cardiac infarction, ulcerative colitis and the like. Nitrones have also been reported to treat certain inflammatory conditions, such as arthritis.
Although various nitrone compounds have been previously reported to be useful as analytical reagents or therapeutic agents, a need exists for novel nitrone spin traps having improved effectiveness ip these applications. For example, when using nitrones as therapeutic agents for treating acute conditions, such as stroke, cardiac infarction or the like, it is particularly desirable to be able to administer the nitrone spin trap at high doses, especially to the localized area immediately surrounding the acute incident, to minimize the amount of free radical-induced oxidative damage that occurs. Thus, nitrone compounds used to treat acute conditions should be non-toxic or have very low toxicity.
Additionally, when studying free radicals in biological systems or when treating various disease conditions caused by free radicals, it is important that the nitrone spin trap have sufficient solubility at the biological site where the free radicals are generated so that the radicals are trapped by the nitrone before they are quenched or cause oxidative damage by their surroundings. Thus, it would be particularly desirable to be able to readily optimize the solubility of nitrone compounds for a particular biological environment ranging in nature, for example, from aqueous to lipophilic.
Accordingly, a need exists for new classes of effective nitrone spin traps having improved properties such as low toxicity and increased solubility in a wide range of biological systems.
This invention provides novel furan nitrone compounds which are effective free radical spin traps and, accordingly, are useful as analytical reagents for detecting free radicals. Additionally, the furan nitrones of this invention have been found to be useful as therapeutics for treating various medical dysfunctions and diseases. In this regard, the furan nitrone compounds have surprisingly low toxicity even at relatively high dosage levels. Structurally, the furan nitrones of this invention are particularly useful as analytical reagents and/or therapeutics since one or more sulfur-derived functional groups are attached to the furan ring thereby allowing the lipophilicity of the compounds to be readily varied. This permits the compounds to be used in a wide variety of biological environments and/or optimized for a particular analytical or therapeutic use.
Accordingly, in one of its composition aspects, this invention is directed to compounds of formula I: 
wherein
each R1 is independently selected from the group consisting of hydrogen, alky, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alky, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of xe2x80x94SO3Y, xe2x80x94S(O)R4, xe2x80x94SO2R5 and xe2x80x94SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alky, substituted alky, alkenyl, alkynyl, alkyl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m+n=3; or pharmaceutically acceptable salts thereof.
Preferably, in the compounds of formula I above, R1 is selected from the group consisting of hydrogen and alkyl. More preferably, R1 is hydrogen.
R2 is preferably selected from the group consisting of hydrogen, alkyl and aryl. More preferably, R2 is hydrogen or alkyl. Still more preferably, R2 is hydrogen.
Preferably, R3 is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl. More preferably, R3 is alkyl or cycloalkyl. Still more preferably, R3 is cycloalkyl. Especially preferred R3 groups are cyclohexyl and isopropyl.
R4 is preferably selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl. More preferably, R4 is alky, aryl or cycloalkyl. Still more preferably, R4 is alkyl.
Preferably, R5 is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl. More preferably, R5 is alkyl, aryl or cycloalkyl. Still more preferably, R5 is alkyl.
X is preferably xe2x80x94SO3Y, xe2x80x94SO2R5 or xe2x80x94SO2NR6R7, wherein R5 is alkyl, cycloalkyl or aryl and R6 and R7 are independently selected from the group consisting of hydrogen, alkyl and cycloalkyl. Alternatively, R6 and R7 are preferably joined together with the nitrogen atom to which they are attached to form a heterocyclic ring having 4 to 6 carbon atoms. More preferably, when X is xe2x80x94SO2NR5R6, R5 is hydrogen and R6 is selected from the group consisting of hydrogen, alkyl and cycloalkyl.
Preferably, m in formula I above is 1 or 2. More preferably, m is 1.
In another of its composition aspects, this invention is directed to a compound of formula II: 
wherein R2, R3, X and m are as defined above, including the above defined preferred embodiments; or pharmaceutically acceptable its thereof.
In still another of its composition aspects, this invention is directed to a compound of formula III: 
wherein
R8 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; and
Y selected from the group consisting of hydrogen and a pharmaceutically acceptable cation.
Preferably, in formula III above, R8 is selected from the group consisting of alkyl, alkaryl, aryl and cycloalkyl. More preferably, R8 is alkyl or cycloalkyl. Still more preferably, R8 is alkyl.
Preferably, in formula III above, Y is hydrogen or a sodium cation.
In yet another of its composition aspects, this invention is directed to the following individual compounds:
N-isopropyl-xcex1-(2-sulfofuran-5-yl)nitrone
N-n-propyl-xcex1-(2sulfofuran-5-yl)nitrone
N-n-butyl-xcex1-(2-sulfofuran-5-yl)nitrone
N-tert-butyl-xcex1-(2-sulfofuran-5-yl)nitrone
N-n-hexyl-xcex1-(2-sulfofuran-5-yl)nitrone
N-cyclohexyl-xcex1-(2-sulfofuran-5-yl)nitrone
N-tert-octyl-xcex1-(2-sulfofuran-5-yl)nitrone
N-benzyl-xcex1-(2-sulfofuran-5-yl)nitrone
N-isopropyl-xcex1-[2-(N-morpholinosulfonyl)furan-5-yl]nitrone
N-isopropyl-xcex1-[2-(N,N-dimethylsulfamoyl)furan-5-yl]nitrone
N-isopropyl-xcex1-[2-(N,N-diethylsulfamoyl)furan-5-yl]nitrone
N-isopropyl-xcex1-[2-(N-4-methylpiperazin-1-ylsulfonyl)furan-5-yl]nitrone
N-tert-butyl-xcex1-[2-(N-3-trifluoromethylphenylsulfamoyl)-furan-5-yl]nitrone
N-tert-butyl-xcex1-[2-(methylsulfonyl)-furan-5-yl]nitrone,
and pharmaceutically acceptable salts thereof.
This invention is also directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I: 
wherein R1-R3, X, m and n are as defined above; or pharmaceutically acceptable salts thereof.
In additional composition aspects, this invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula II or III above.
As previously mentioned, the furan nitrone compounds of this invention have been found to be effective free radical spin traps. As such, these compounds are useful as analytical reagents for detecting free radicals. Additionally, the furan nitrones of this invention have been discovered to be useful as therapeutics for treating a wide variety of medical dysfunctions and diseases including, but not limited to, acute central nervous system (CNS) disorders, acute cardiovascular disorders, neurodegenerative conditions, inflammatory diseases and autoimmune conditions.
Accordingly, in one of its method aspects, this invention provides a method for treating a patient with an acute central nervous system disorder, said method comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective acute central nervous system disorder-treating amount of a compound of formula I above. In a preferred embodiment of this method, the acute central nervous system disorder treated is stroke.
In another of its method aspects, this invention provides a method for treating a patient with an acute cardiovascular disorder, said method comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective acute cardiovascular disorder-treating amount of a compound of formula I above. In a preferred embodiment of this method, the acute cardiovascular disorder treated is cardiac infarction.
In still another of its method aspects, this invention is directed to a method for treating a patient with a neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective neurodegenerative disease-treating amount of a compound of formula I above. Additionally, this invention is directed to a method for preventing the onset of a neurodegenerative disease in a patient at risk for developing the neurodegenerative disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective neurodegenerative disease-preventing amount of a compound of formula I above.
In preferred embodiments of this invention, the neurodegenerative disease treated and/or prevented in the above methods is Alzheimer""s disease, Parkinson""s disease, HIV dementia and the like.
In yet another of its method aspects, this invention is directed to a method for treating a patient with an autoimmune disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective autoimmune disease-treating amount of a compound of formula I above. This invention is also directed to a method for preventing the onset of an autoimmune disease in a patient at risk for developing the autoimmune disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective autoimmune disease-preventing amount of a compound of formula I above.
In preferred embodiments of this invention, the autoimmune disease treated and/or prevented in the above methods is systemic lupus, multiple sclerosis and the like.
In still another of its method aspects, this invention is directed to a method for treating a patient with an inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-treating amount of a compound of formula I above. Additionally, this invention is directed to a method for preventing the onset of an inflammatory disease in a patient at risk for developing the inflammatory disease which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective inflammatory disease-preventing amount of a compound of formula I above.
In preferred embodiments of this invention, the inflammatory disease treated and/or prevented in the above methods is rheumatoid arthritis, septic shock, erythema nodosum leprosy, septicemia, uveitis and the like.
This invention is also directed to processes for preparing the furan nitrone compounds of formula I. Accordingly, in one of its process aspects, this invention provides a process for preparing a compound of formula I: 
wherein
each R1 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each X is independently selected from the group consisting of xe2x80x94SO3Y, xe2x80x94S(O)R4, xe2x80x94SO2R5 and xe2x80x94SO2NR6R7;
wherein Y is hydrogen or a pharmaceutically acceptable cation;
R4 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alknyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m+n=3, said process comprising reacting a furan carbonyl compound of the formula: 
with a hydroxylamine of the formula:
HOxe2x80x94NHxe2x80x94R3
to provide a compound of formula I.
In another of its process aspects, the present invention provides a process for preparing a sulfamoyl-substituted furan nitrone of formula Ixe2x80x2: 
wherein
each R1 is independently selected from the group consisting of hydrogen, allyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkoxy, alkcycloalkyl, cycloalkyl, cycloalkenyl and halo;
R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
R3 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl;
each Xxe2x80x2 is xe2x80x94SO2NR6R7; wherein R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkynyl, alkaryl, aryl, alkcycloalkyl, cycloalkyl and cycloalkenyl; or R6 and R7 together with the nitrogen atom to which they are attached can form a heterocyclic ring containing from 2 to 8 carbon atoms and optionally from 1 to 3 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;
m is an integer from 1 to 3; and n is an integer from 0 to 2, provided that m+n=3, said process comprising the steps of:
(a) reacting a carbonyl-substituted furan sulfonic acid compound of the formula: 
xe2x80x83with phosphorous trichloride and phosphorous pentachloride to provide a gem-dichloride-substituted furan sulfonyl chloride compound of the formula: 
(c) reacting the gem-dichloride-substituted furan sulfonyl chloride compound with an amine of the formula: 
xe2x80x83to provide a gem-dichloride-substituted furan sulfonamide compound of the formula: 
(c) hydrolyzing the gem-dichloride-substituted furan sulfonamide compound to provide a carbonyl-substituted furan sulfonamide compound of the formula: 
xe2x80x83and;
(d) reacting the carbonyl-substituted furan sulfonamide with a hydroxylamine of the formula:
HOxe2x80x94NHxe2x80x94R3
xe2x80x83to provide a compound of formula Ixe2x80x2.
In another of its aspects, this invention is directed to the use of a compound of formula I, II or III above in the manufacture of a formulation or medicament for a medicinal treatment. Preferably, the medical treatment is the therapeutic or prophylactic treatment of an acute central nervous system disorder, an acute cardiovascular disorder, a neurodegenerative disease, an autoimmune disease or an inflammatory disease.